This invention relates to certain novel difluorophthalic compounds and to the preparation of those compounds and related compounds. In particular, it relates to 3,5-difluorophthalic anhydride, imide, acid, and salts, esters, and half-esters of the acid and to the preparation of those compounds and the use of those compounds to prepare 3,5-difluorobenzoic acid and 3,5-difluorobenzene.
A variety of uses are known for 3,5-difluorobenzoic acid as a chemical intermediate. For example, it can be used as an intermediate in the synthesis of liquid crystal additions, fungicides, organo-tin antitumor compounds, insecticides, and quinolones. The compound 1,3-difluorobenzene can be used in the synthesis of antifungal agents, pharmaceuticals, dyes, and agrochemicals.
3,5-Difluorobenzoic acid has been prepared from 2,4-difluoroaniline. Bromination, followed by deamination with nitrous acid, led to 3,5-difluorobromobenzene. This was transformed by a Grignard reaction (magnesium, followed by the addition of CO.sub.2). J. Org. Chem., 20 (1955) 1577. A second synthesis of 3,5-difluorobenzoic acid started with 3,5-difluorobromobenzene. This was treated with butyllithium followed by the addition of CO.sub.2. CA(73): 77636. Both of these methods suffer from numerous steps and the unavailability of the starting material in commercial quantities.
1,3-Difluorobenzene can be prepared by diazotization of 1,3-diaminobenzene. This method requires a large number of steps and the starting material, 1,3-dichlorobenzene, is expensive and difficult to synthesize in large amounts. The diazotization reaction is somewhat dangerous due to the formation of intermediate diazo compounds and the use of sodium nitrite, a potentially explosive reagent, in the deamination reaction. In addition, the synthesis uses an expensive palladium catalyst in the reduction of the nitro group to the amine. A similar synthesis starts from the less expensive 1,2,4-trichlorobenzene, but still requires the use of an expensive palladium catalyst and a deamination reaction (Synth. Commun., 24(4), 529(1994)).
A second method for the synthesis of 1,3-difluorobenzene involves chlorodenitration of 2,4-difluoronitrobenzene, followed by catalytic hydrogenation of the resultant chlorodifluorobenzene. This method, although avoiding the problematic diazotization reactions, suffers due to the number of steps involved, as well as the use of chlorine gas and an expensive palladium catalyst (JP 03077836; CA 115(15):158695h).